Oleanolic acid (OA), also known as caryophyllin, is a type of pentacyclic triterpenoids. It is extracted from the leaves and fruits of Oleaceae, Gentianaceae, Rubiaceae, Amaranthaceae, and the like, and is mainly present in free form and (or) in combination with saccharides. Many scientists, domestic and overseas, have conducted extensive research on pentacyclic triterpenoids. According to the literature, oleanolic acid and derivatives or analogs thereof exhibit a variety of biological activities, such as anti-inflammation, antitumor, antivirus, immunoregulation, inhibition of platelet aggregation, hypolipidemic, liver protection, kidney protection, anti-HIV, etc. (LI, Yingxia et al., An oleanolic acid-lactose conjugate, the preparation process and use thereof, [P] CN 1414012 A. 2003; ZHANG, Yihua et al., An oleanolic acid derivative, the preparation process and use thereof, [P] CN 102070697 A. 2011; Lin, Z. H.; Zhang, Y.; Zhang, Y. N.; Shen, H.; Hu, L. H.; Jiang, H. L.; Shen, X. Oleanolic acid derivative NPLG441 potently stimulates glucose transport in 3T3-L1 adipocytes via a multi-target mechanism. Biochemical Pharmacology. 2008. 76:1251-1262; Chen, J.; Gong, Y. C.; Liu, J.; Hua, W. Y.; Zhang, L. Y.; Sun, H. B. Synthesis and biological evaluation of novel pyrazolo[4,3-b]oleanane derivatives as inhibitors of glycogen phosphorylase. Chemistry & Biodiversity. 2008. 5: 1304-1312).

Nowadays, malignant tumor is the most serious common disease and poses threats to human health. The development of anti-tumor drugs is an important research topic of modern medicine. It has become a focus of the anti-tumor research domestic and overseas to search for drugs with high efficacy and low toxicity from Chinese herbal plants. Oleanolic acid, with low toxicity and having abundant resource in Chinese herbal medicine, is a very promising anti-tumor drug.
Recent years witnessed the literature report of oleanolic acid for its function against human lung cancer cell proliferation, and its ability of anti-invasion and inducing cell apoptosis. Researchers observed the effects of oleanolic acid on the invasion ability of PGCL3 cells through cell proliferation inhibition assay, soft agar colony formation assay, and the like. Results showed that oleanolic acid could reduce proliferation of PGCL3 cells in a dose-dependent correlation, had the effects of anti-proliferation and anti-invasion of PGCL3 human lung cancer cells, and had the effect of inducing apoptosis of PGCL3 cells. Its anti-invasion effect lies not only in the blocking of a particular step of the invasion, but the inhibition of each basic step of the invasion. In addition, researchers explored the effect of oleanolic acid on A549 cells and the possible mechanism thereof, and the results showed that oleanolic acid was capable of a concentration-dependent induction of apoptosis of human lung adenocarcinoma cells. (ZHANG Dongfang et al., Study on proliferation inhibition and anti-invasion and apoptotic induction of oleanolic acid in human lung cancer cell line, 2003, 30 (3): 081-381; WEI Xiaohong et al., Apoptosis induced by oleanolic acid and its relation to intracellular calcium of human lung adenoma A549 cells, Journal of Tongji University (Medical Science), 2009, 30 (5): 19-23.)
Literature reported that researchers studied the inhibition of ovarian cancer cell line IGROV1 and human breast cancer cell line MDA-MB-231 by oleanolic acid via detecting the activity of tumor cells through inhibition tests of cell proliferation and MTT method. The results showed that oleanolic acid could reduce the proliferation ability of IGROV1 and MDA-MB-231 cells in a dose-dependent correlation, which indicated that oleanolic acid had inhibitory activity against these two malignant tumor cell lines. (WU, Linwei et al., Inhibiting Effect of Oleanolic Acid on Ovarian Carcinomas IGROV1 and Breast Cancer Cell Line MDA-MB-231, Chinese Journal of Applied and Environmental Biology, 2010, 16(2): 202-204.)
Recently, LIN Xiukun et al. reported the excellent anti-pancreatic cancer effects of oleanolic acid and pharmaceutical preparations thereof, which was represented by the obvious inhibitory activity on human pancreatic cancer cells in vitro and the significant antitumor activity on nude mice with transplanted tumor of these tumor cells. In addition, LIN Xiukun et al. also studied the inhibitory effect of oleanolic acid on cervical cancer. The results showed that oleanolic acid and pharmaceutical preparations thereof had obvious in vitro inhibitory activity on human cervical carcinoma cells and also had significant antitumor activity on transplanted tumor in nude mice of these tumor cells. (LIN Xiukun et al., Anti-pancreatic carcinoma effects of oleanolic acid and pharmaceutical preparations thereof, [P] CN 102151275 A. 2011; LIN Xiukun et al., Anti-cervical cancer effects of oleanolic acid and pharmaceutical preparations thereof, [P] CN 102133219 A. 2011.)
Oleanolic acid is widely applied in clinics due to its various pharmacological activities and low toxicity, but this type of drug has low bioavailability in a human body. Therefore, oleanolic acid derivatives with high efficiency and low toxicity have good prospects in industry. The present invention modified oleanolic acid on its C-17 position by amino substitution and introduced functional groups to improve its biological activity and bioavailability. Up to now, report on the method of the present invention and the amidated derivatives of oleanolic acid by amino-substitution on C-17 position have not yet been seen in the literature.